Mechanism found for destruction of key allergy-inducing complexes, researchers say
Researchers have learned how a man-made molecule destroys complexes that induce allergic responses — a discovery that could lead to the development of highly potent, rapidly acting interventions for a host of acute allergic reactions.
The new inhibitor disarms IgE antibodies, pivotal players in acute allergies, by detaching the antibody from its partner in crime, a molecule called FcR. (Other mechanisms lead to slower-developing allergic reactions.)
“It would be an incredible intervention if you could rapidly disconnect IgE antibodies in the midst of an acute allergic response,” said Ted Jardetzky, PhD, professor of structural biology and senior investigator for the study. It turns out the inhibitor used by the team does just that.
A myriad of allergens, ranging from ragweed pollen to bee venom to peanuts, can set off IgE antibodies, resulting in allergic reactions within seconds. The new inhibitor destroys the complex that tethers IgE to the cells responsible for the reaction, called mast cells. Severing this connection would be the holy grail of IgE-targeted allergy treatment.
The first time a potential allergen enters the body, some people respond by making allergen-specific IgE antibodies. These antibodies stick around long after the initial allergen is cleared from the body. Most of the antibodies get snagged by IgE-specific receptors called FcRs, which are exposed on the surface of mast cells. The mast cells are then primed to react the next time a person encounters the allergen.
Dissociation of this IgE-FcR interaction is a sought-after goal of allergy treatment for a good reason: IgE-coated mast cells are grenades of histamine, and re-encountering the allergen is equivalent to pulling out the clip. When an allergen makes a return visit, it binds to the pre-loaded IgE on the mast cell surface, triggering the release of inflammatory mediators — including histamine — that promote the allergic response. As allergy sufferers are well aware, these nasty reactions can occur within a matter of seconds. In a severe allergic response, sudden anaphylactic shock and death can be the result.
The key to actively disabling the allergic response lies in the separation of IgE from the FcRs on the surface of mast cells. But separating these dangerous couples is a tall order because their interaction is extremely stable — sensitizing the mast cells for weeks. Currently available treatment using omalizumab (an anti-IgE antibody sold under the trade name Xolair) can block new interactions between IgE and FcR, but it is not designed to pry the molecules apart once they’ve formed a bond on the surface of a mast cell. So Xolair can dampen the allergic response, but as stated on the product’s website: “Xolair is not a rescue medicine and should not be used to treat sudden asthma attacks.”
While simply blocking IgE binding is helpful for some allergy sufferers, when it comes to the rapid quenching of an acute allergic response, “what you’d really like to do is get rid of it,” said Jardetzky. Along with scientists at the University of Bern, his team discovered that an engineered protein inhibitor called DARPin E2-79 stripped IgE from the mast cell receptor. Using this inhibitor, “an interaction that normally lasts for hours or days in terms of its stability is stripped off in a matter of seconds,” said Jardetzky.